PROJECT SUMMARY (Project 2 ? Orthodontic Trial in OI) Our previous studies have shown that approximately 80% of individuals with osteogenesis imperfecta (OI) type III and IV (the moderate to severe forms of OI) have dental malocclusion. This is a major unmet medical need as malocclusion interferes with speech, the ability to chew and detrimentally impacts on the quality of life. There are no evidence-based treatment options for malocclusion in OI. In our clinical practice we have treated malocclusion in 3 adolescents with OI types III and IV using Invisalign, a widely used FDA- approved approach to treat malocclusion (Class II device). Invisalign is typically used to treat adolescents or young adults with malocclusion of intermediate severity. The severity of malocclusion can be determined using the Peer Assessment Rating (PAR) score. PAR scores between 15 and 40 are considered intermediate severity. We propose to perform a multicenter study to evaluate the efficacy and safety of Invisalign for the treatment of malocclusion in OI. We will assess the improvement in malocclusion in a 6-month randomized study, followed by an open-label extension study that evaluates the outcome of a full 24-months Invisalign treatment course. Aim 1 is to determine whether 6 months of treatment with the Invisalign system improves the malocclusion compared to an untreated control group (randomized trial). We will enroll individuals with OI type III or IV from 12 to 40 years of age who have malocclusion of intermediate severity. Subjects will be assigned to either receive Invisalign treatment (treatment group) or to be followed without orthodontic treatment (control group) (n = 18 per group). Randomization will be stratified according to OI type, age and bisphosphonate treatment status. The primary endpoint will be the change in PAR score; secondary endpoints will include anatomical tooth movement. The hypothesis is that the treatment will induce tooth movement and have a significantly larger decrease in mean PAR score (indicating improved malocclusion) than the control group. Aim 2 of the study is to determine whether a full treatment course of Invisalign treatment improves oral-health related quality of life (extension study). After the first 6 months of randomized therapy, all participants will have Invisalign treatment. The total treatment period will be 24 months (+/- 6 months, based on achieving the treatment goals specified at baseline). The primary study endpoint will be change in oral-health related quality of life. Secondary endpoints will be changes in mastication, expressed anatomically as the number of occlusal contacts, and masticatory efficiency, a functional parameter, as well as patient satisfaction. The hypothesis is that oral health-related quality of life and mastication will improve over the Invisalign treatment course. This study will provide for the first time scientific evidence on how to treat malocclusion in the context of OI. If successful, this approach can be rapidly implemented into clinical practice.